Bacteria adapted to mucosal surfaces commonly produce lipooligosaccharide endotoxins, many of which contain host glycolipid epitopes. Work in Dr. Swords' laboratory has established that one such epitope, phosphorylcholine, profoundly changes host-pathogen interactions for the bacterium Haemophilus influenzae. Our show that this modification reduces host innate responses to endotoxins. We hypothesize that phosphorylcholine weakens a proximal event in endotoxin recognition by the Toll-like receptor 4 (TLR4) complex. In order to address this hypothesis, we will complete the following Specific Aims: 1) Delineate how phosphorylcholine affects host innate responses in vitro. 2) Define how phosphorylcholine affects the events leading to activation of Toll-like receptor-4. Haemophilus influenzae is one of a group of host-adapted commensals that cause opportunistic airway infections when innate defenses are compromised. Understanding how the host normally contains these bacteria within the nasopharynx, how the bacteria are adapted to persist in the face of host clearance, and how host-pathogen interactions are changed during opportunistic infections are important landmarks in the development of new strategies to prevent or treat these infections. Thus, the work in this proposal presents an important opportunity to address infections that are a significant public health concern.